The present invention relates generally to compositions and methods for treating or preventing bacterial infections, and more specifically to treating or preventing infections caused by extreme drug resistant bacteria expressing a carbapenemase.
In the last decade, multi-drug resistant organisms have become endemic in healthcare systems throughout the world. Of highest priority for new treatment strategies are infections caused by extreme drug resistant (XDR) gram negative bacilli, which are resistant to carbapenems and all other antibiotics except for colistin or tigecycline. For example, infections caused by XDR Klebsiella pneumoniae that express the serine carbapenemase K. pneumonia carbapenemase (KPC) have spread across the United States. Moreover, infections caused by these KPC bacteria are associated with an approximate 50% mortality rate. Like KPC, a recently identified metallo-β-lactamase resistance mechanism termed the New Delhi metallo-β-lactamase (NDM-1), which is spread by transmissible plasmids, has been found globally. For example, NDM-1 bacteria have been found in Asia, Western Europe and the United States. The global health concerns regarding these bacteria are even further exacerbated by the dearth of drugs in the commercial pipeline that may have activity against these organisms.
KPC-expressing K. pneumoniae are increasingly common and cause substantial morbidity and mortality. The initial outbreak of carbapenem-resistant K. pneumoniae expressing the KPC enzyme occurred in North Carolina in 1996. Yigit et al., Antimicrob. Agents Chemother. 45:1151-1161 (2001). Shortly thereafter the organism appeared in New York City, where it has since become endemic in hospitals. Bratu et al., Antimicrob Agents Chemother. 49:3018-3020 (2005); Gootz et al. Antimicrob. Agents Chemother. 53:1998-2004 (2009); Bradford et al., Clin. Infect. Dis. 39:55-60 (2004) and Woodford et al., Antimicrob. Agents Chemother. 48:4793-4799 (2004). For example, in just two months, four hospitals in Brooklyn, N.Y. cultured more than sixty KPC-expressing isolates of K. pneumoniae, which represented a quarter of all the K. pneumoniae isolates encountered. Bratu et al., supra. Subsequently KPC-expressing isolates spread to most states in the United States, as well as through Europe, Asia, and Latin America. Kitchel et al., Antimicrob. Agents Chemother. 53:3365-3370 (2009); Zarkotou et al., Clin. Microbiol. Infect. 17(2):1798-1803 (2011); Cuzon et al., Antimicrob. Agents Chemother. 52:796-797 (2008); Navon-Venezia et al., Antimicrob. Agents Chemother. 53:818-820 (2009); Kitchel et al., Antimicrob. Agents Chemother. 53:4511-4513 (2009); Qi et al., J. Antimicrob. Chemother. 66:307-312 (2011); Villegas et al., Antimicrob. Agents Chemother. 50:2880-2882 (2006); and Deshpande et al., Diagn. Microbiol. Infect. Dis. 56:367-372 (2006). The US Centers for Disease Control reported the molecular typing results of strains they had accumulated from thirty-three US states, as well as Israel and India. Kitchel et al., Antimicrob. Agents Chemother. 53:3365-3370 (2009). A single strain type, ST 258, accounted for 70% of these isolates.
The most common sites of infection caused by KPC-expressing bacteria include the lung, the blood, and the abdomen, although other sites may be involved as well (e.g., urine and wounds). Gasink et al., Infect. Control Hosp. Epidemiol. 30:1180-1185 (2009). By multivariate analysis, risk factors for acquisition of KPC-expressing K. pneumoniae, compared to carbapenem-susceptible bacteria, included severe illness (odds ratio [OR] 4), prior fluoroquinolone use (OR 3), and prior extended-spectrum cephalosporin use (OR 3). Gasink et al., supra; and Schwaber et al. Antimicrob. Agents Chemother. 52:1028-1033 (2008). In another study, infection caused by KPC-expressing K. pneumoniae was independently associated with receipt of mechanical ventilation, longer length of stay before infection, and exposure to cephalosporins and carbapenems. Patel et al., Infect. Control Hosp. Epidemiol. 29:1099-1106 (2008).
In multiple studies, infection caused by KPC-producing K. pneumoniae was independently associated with in-hospital mortality. In several case control studies, absolute in hospital mortality rates of patients infected with KPC-expressing K. pneumoniae ranged from 32 to 44% versus 9 to 13% mortality rates for infections caused by carbapenem-susceptible K. pneumoniae. Gasink et al., supra; Schwaber et al., supra; and Patel et al., supra. In a case series from New York, the in hospital mortality of patients bacteremic with KPC-expressing K. pneumoniae was ˜50%. Bratu et al., supra; Zarkotou et al., supra; and Patel et al., supra. The mortality was even worse (61%) in patients infected with KPC-expressing K. pneumoniae who received initially ineffective therapy. Zarkotou et al., supra. In another case series, the mortality rate of patients infected by KPC-expressing K. pneumoniae was 59% among patients in the intensive care unit and 38% among non-ICU patients. Souli et al. Clin. Infect. Dis. 50:364-73 (2010).
Even worse outcomes are seen with truly pan-drug resistant strains. For example, in a case control study of patients with colistin susceptible vs. colistin resistant KPC expressing K. pneumoniae, the mortality rate of patients with colistin-susceptible strains was 54%. Zarkotou et al., supra. By comparison, the mortality rate of patients with colistin-resistant strains was an alarming 75%. These unacceptably high mortality rates, and the rising incidence of KPC-expressing strains and pan-resistance among those strains, underscore the need for new therapeutic strategies to deal with these infections.
NDM-1-expressing gram negative bacteria are also spreading rapidly and globally. The initial description of NDM-1 occurred in a Swedish patient of Indian descent who acquired a urinary tract infection (UTI) during a trip to New Delhi. Yong et al., Antimicrob. Agents Chemother. 53:5046-5054 (2009). The follow up case series described isolates of both E. coli and K. pneumoniae expressing NDM-1 found throughout India. Kumarasamy et al., Lancet Infect. Dis. 10:597-602 (2010). Numerous patients brought their infections back to Europe. The strains were all resistant to all antibiotics except tigecycline and colistin, and up to 10% of the strains were resistant to both of these antibiotics and were pan-drug resistant (PDR) strains. Since then bacteria from numerous other genera, including Enterobacter, Acinetobacter, Shigella, Vibrio, Aeromonas, and Pseudomonas, have been described to express NDM-1. Moreover, these organisms have been found throughout China, Japan, Europe, Africa, Canada, Australia, and in the United States. Moellering et al., N. Engl. J. Med. 363:2377-2379 (2010); Castanheira et al., Antimicrob. Agents Chemother. 55:1274-8 (2011); Poirel et al., Antimicrob. Agents Chemother. 54:4914-4916 (2010); Poirel et al., Antimicrob. Agents Chemother. 55:934-936 (2011); Struelens et al., Euro. Surveill. 15(46): pii: 19716 (2010); Bonomo, Clin. Infect. Dis. 52:485-487 (2011); Tijet et al., Emerg. Infect. Dis. 17:306-307 (2011); Chen et al., J. Antimicrob. Chemother. 66:1255-1259 (2011); and Yamamoto et al., J. Infect. Chemother. 17:435-439 (2011). NDM-1-expressing gram negative bacilli have also been cultured from foreign nationals cared for in forward deployed military medical units, creating potential for their transfer to US military personnel. Ake et al., Infect. Control Hosp. Epidemiol. 32:545-552 (2011); and Sutter et al., Infect. Control Hosp. Epidemiol. 32:854-60 (2011).
In addition to spreading into multiple genera, individual E. coli strains expressing NDM-1 have been found to be of multiple strain types, underscoring the ecological diversity of the resistance mechanism. Mushtaq et al., J. Antimicrob. Chemother. 66:2002-2005 (2011). Unfortunately, diverse genera expressing NDM-1 have been found widely distributed in environmental sources throughout India, underscoring the ability of the organism to spread in communities outside of a healthcare setting. Walsh et al., Lancet Infect. Dis. 11:355-362 (2011); and Peirano et al., Emerg. Infect. Dis. 17:242-244 (2011). NDM-1 will likely continue to spread both in communities and in healthcare settings in the United States, and throughout the world.
Thus, new ways to prevent or treat infections caused by XDR gram negative bacilli are needed. This invention satisfies this need and provides related advantages.